Expiratory flow limitation during mechanical ventilation: real-time detection and physiological subtypes

Background Tidal expiratory flow limitation (EFLT) complicates the delivery of mechanical ventilation but is only diagnosed by performing specific manoeuvres. Instantaneous analysis of expiratory resistance (Rex) can be an alternative way to detect EFLT without changing ventilatory settings. This study aimed to determine the agreement of EFLT detection by Rex analysis and the PEEP reduction manoeuvre using contingency table and agreement coefficient. The patterns of Rex were explored. Methods Medical patients ≥ 15-year-old receiving mechanical ventilation underwent a PEEP reduction manoeuvre from 5 cmH2O to zero for EFLT detection. Waveforms were recorded and analyzed off-line. The instantaneous Rex was calculated and was plotted against the volume axis, overlapped by the flow-volume loop for inspection. Lung mechanics, characteristics of the patients, and clinical outcomes were collected. The result of the Rex method was validated using a separate independent dataset. Results 339 patients initially enrolled and underwent a PEEP reduction. The prevalence of EFLT was 16.5%. EFLT patients had higher adjusted hospital mortality than non-EFLT cases. The Rex method showed 20% prevalence of EFLT and the result was 90.3% in agreement with PEEP reduction manoeuvre. In the validation dataset, the Rex method had resulted in 91.4% agreement. Three patterns of Rex were identified: no EFLT, early EFLT, associated with airway disease, and late EFLT, associated with non-airway diseases, including obesity. In early EFLT, external PEEP was less likely to eliminate EFLT. Conclusions The Rex method shows an excellent agreement with the PEEP reduction manoeuvre and allows real-time detection of EFLT. Two subtypes of EFLT are identified by Rex analysis. Trial registration: Clinical trial registered with www.thaiclinicaltrials.org (TCTR20190318003). The registration date was on 18 March 2019, and the first subject enrollment was performed on 26 March 2019. Supplementary Information The online version contains supplementary material available at 10.1186/s13054-024-04953-9.


Table of contents
Table S1: Baseline ventilator settings, parameters, and lung mechanics at baseline Table S2: The presence of EFLT at ZEEP and at PEEP level ≥ 5 cmH2O Table S3: The agreements between the Rex method and the PEEP reduction (FLOWLY study) Table S4: Characteristics of patients in the validation set for Rex analysis (FLOWLY study) Table S5: The distribution of the anatomical site of pathology between each subtype of EFLT

Section E: Examples of cases and additional materials for discussion
Table E1: The agreements between the "delta Vte only" VS the "full criteria" Table E2: Response to external PEEP application among patients with 2 subtypes of EFLT  2) The informed-consent could be obtained and EFLT detection manoeuvres began within 48 hours after the ventilator connection 3) Permission from the attending doctor to go through the study manoeuvre was granted

Section S2: Sample size calculation
One of the well-known factors associated with EFLT in previously reported studies is obesity (BMI ≥ 30 kg/m 2 ) [Ref E1,E2,E3,E4,E5].However, the prevalence of obesity in Asian population is much lower than those observed in western countries.Since there was no study to depict the prevalence of EFLT in our population, we initially aimed to perform the study for 1 year.After 7 months of recruitment and 217 analyzable cases had been collected, we performed an interim data analysis.
The prevalence of EFLT by the PEEP reduction method was about 13% (11.3% in non-obese and 38.5% in obese patients).The preliminary multivariable analysis had determined that the previouslydescribed factor, BMI ≥ 30 kg/m 2 , had the odds ratio of 2.74 (95%CI 0.67-11.22)to predict the EFLT (p= 0.161).This was caused by the low prevalence of obese patients (13 out of 217 cases, i.e. 6.0%).We thus calculated the sample size needed to determine the effect of obesity to predict the presence of EFLT using the following formula [Ref E6]: We aimed for 20% power (β = 0.2, Zβ = 0.84), with 95% confidence interval (α = 0.05, Zα = 1.96).
The parameters q0 and q1 are the proportion of non-obese and obese patients, respectively (q0 = 0.94, q1 = 0.06).P0 and P1 are prevalence of EFLT in the two groups (0.113 and 0.385, respectively), where P = pooled proportion = 0.13.In previous literatures using PEEP reduction manoeuvre, there was no consensus regarding the level of initial PEEP level to be used in the manoeuvre.Also, the level of PEEP change (difference between the initial PEEP and the test PEEP) seems to be varied, and the value of 2, 3, or 6 cmH2O has been reported for EFLT detection [Ref E4,E5,E8,E9,E10].
During our pilot analysis with PEEP reduction manoeuvre from various initial PEEP levels (between 5 -10 cmH2O) to ZEEP, there were conflicting results when different set-PEEP were used in the same patient.In some patients with clinically suspected EFLT (e.g., substantial PEEPi with PEEP absorption behavior), PEEP reduction from the level that was greater than the measured PEEPi showed negative results.In these same patients, repeated test with an initial set-PEEP level lower than or close to the PEEPi yielded positive results.The findings suggested that using too high initial set-PEEP could yield a false-negative result, as the manoeuvre might not be able to detect EFLT that occurs below the level of an initial set-PEEP.In a small study (10 patients) using PEEP reduction method, the PEEP level was reduced only by 2 cmH2O from the reference breath and EFLT was considered to exist if the test flow curve overlapped with the reference flow curve for >10% of the volume slice [Ref E10].In our study which utilized PEEP reduction of 5 cmH2O, the flow was expected to be increased at a larger extent and the portion that overlaps with the reference was expected to be less.We then decided to define EFLT with lower threshold of overlapping, i.e., 5% instead of 10% Vte.
With pilot data collection, we have found that within the same EFLT patient underwent PEEP reduction, the Flow-Volume curve of the test breath might completely overlap with the reference, or it might be a little bit higher, running close and parallel to that of the reference breath (Figure 1, main text).In order to allow the flow variation in EFLT cases, we calculated the 10% of the reference breath's peak expiratory flow (PEF).This derived value would then be added to the reference flow to generate an envelope of reference flow + 10% PEF.This gave the preliminary EFLT criterion: a test breath showing an expiratory Flow-Volume curve with ≥ 5% of Vte running within the threshold of REF curve + 10%PEF (i.e., within the envelope of the dashed line).
However, there were a number of non-EFLT cases with subtle increase of the expiratory flow during PEEP reduction, which might be misclassified as EFLT cases.In this case, a significant portion of

The addition of the delta Vte criterion
We determined the "delta Vte" or the difference between the Vte of the test breath and the reference breath during a PEEP reduction test.
In non-EFLT case, the Vte in the test breath would increase compared to the reference breath due to its lower end-expiratory lung volume (EELV) being at lower PEEP level.In EFLT, however, due to the trapped air at the upstream segment of the choke point, the EELV is virtually the same as the reference.The Vte of the test breath in EFLT cases thus minimally increase or being the same as the test breath ("minimal delta Vte").The cut-off point of this delta Vte has never been reported.
In order to compare the delta Vte in non-EFL VS EFL patients, we have explored our cases with definite non-EFLT (no significant overlap of the curves even with the REF + 10%PEF envelope) VS cases with definite EFLT (significant overlap with the original F-V curve of the reference breath). Section S4: development of EFLT criteria for PEEP the reduction manoeuvre We had found the best cut-off point of delta Vte that can distinguish the EFLT and non-EFLT cases to be 18.7% of the reference Vte.This was pragmatically rounded to 20%.

The finalized criteria for EFLT by PEEP reduction manoeuvre
End of the Section S4: development of EFLT criteria for the PEEP reduction manoeuvre EFLT at ZEEP is present when the PEEP reduction manoeuvre from 5 cmH2O to ZEEP produces these results: (1) the flow-volume curve of the test breath has a significant portion (≥ 5% of the reference Vte) running within the envelope of the reference breath's flow +10% of the reference peak expiratory flow (PEF); and, (2) the increased exhaled tidal volume during the PEEP reduction (during the test breath) is less than 20% of the reference breath. Section S5: development of EFLT criteria for the Rex method Section S5:

Development of EFL T criteria for the Rex method
From our hypothesis that, in the case with EFLT, the instantaneously calculated expiratory airway resistance (Rexi) should substantially increase to a higher level than the inspiratory resistance (Rin).However, the exact threshold is lacking.
During preliminary analysis, we have observed that, except for the initial part of Rex curve just before the "elbow" point, the Rex curve would form a constant line (approximately) equals to the value of Rin.However, just like the variation of the flow in the PEEP reduction manoeuvre (see section S4), the variation also exists in the Rex measurements.Moreover, based on physiologic grounds, the Rex should probably be higher than the Rin due to the reduction of the airways diamater during expiration.This implies that there should be a margin related to the Rin value to be determined.We have selected 283 non-EFLT cases (classified by the PEEP reduction manoeuvre from 5 cmH2O to ZEEP) and analyzed the relationship between the Rex and Rin found in the Rex analysis of these patients at ZEEP. 3.This will then be compared to the "Plateau Rin" of that breath.The Rex and Rin value from all representative breaths of non-EFLT cases were analyzed using a linear correlation and the Bland-Altman plot.

Constant part of Rex
The "elbow" point Rex average value (from the blue line) = 10.28 cmH  Section S5: development of EFLT criteria for the Rex method The relationship between the Rex and Rin in the selected cases The Rex was analyzable in 281 out of 283 non-EFLT cases.There were 775 pairs of Rex and Rin available for comparison.
From the Bland-Altman plot, the mean difference of the Rex and Rin is almost equal to zero (-0.83), while the ±1.96SD range of the difference is +7.62 to -9.29.For pragmatic reason, we had rounded the difference to be ±10 cmH2O/L/s.This converts to the threshold of Rex: "Rex being 10 cmH2O/L/s or more above the Rin would suggest an EFLT state".
In order to be consistent with the EFLT criteria of the PEEP reduction manoeuvre, the Rexi has to stay above the threshold for ≥ 5% of Vte to be significant enough to be judged as having EFLT.
We have finally defined the operational criteria to classify EFLT by the Rex method as followed.

End of the Section S5: development of EFLT criteria for the Rex method
EFLT at a particular PEEP level is defined when the Rex analysis performed at that PEEP level shows: "A breath where the Rexi value progressively increases along the expiration, to the value significantly higher (> 10 cmH2O/L/s) than the plateau of its Rin for ≥ 5% of the Vte" Pearson correlation 0.556 (P < 0.001) Section S6: FLOWLY study (validation set for Rex analysis) The validation set was derived from the data collected in another study: Screening expiratory flow limitation by flow-time curve (FLOWLY).The trial was a single-center, prospective, physiological study conducted at St. Michael's Hospital, Toronto, ON, Canada.Brief details of the study are as follow:

Primary objective:
To test the hypothesis that various parameters derived from flow-time curve can accurately detect the EFL in real time during mechanical ventilation.

Secondary objective:
To test whether the above parameters correlate with the severity of EFL.
Receiving invasive mechanical ventilation in assist/control mode with PEEP ≥ 5 cmH2O 3.
Displaying a monotonous regular breathing pattern with no obvious asynchrony Exclusion criteria: 1.

Brief study procedures
Once patients are confirmed to meet the inclusion criteria, the patient will be continued to ventilate with their current clinical settings / mode and determine the stability of inspiratory tidal volume (defined by ≤10% variation of the tidal volume between each breath over 5 breaths).PEEP was abruptly reduced by 5 cmH2O for 3-4 breaths, for two episodes, 5 minutes apart.This allowed diagnosing EFL, using a flow-volume loop during off-line analysis.The end-expiratory and end-inspiratory pause (lasting 2 seconds each) was performed to assess the total PEEP and plateau pressure for the determination of lung mechanics.

Data recording and analysis
The flow and pressure waveforms were collected via Servo ventilators using Servo Tracker v4.1 (Maquet Critical Care AB, Sweden) or from the dedicated pneumotachometer (MP150 systems and AcqKnowledge v4; BIOPAC Systems, Inc., CA, USA) attached to the circuit.The refresh rate was adjusted to 100Hz for Rex analysis using the same software used in the MAFAI VENT study (MAFAI VENT waveform analyzer v 2.74).

Ethical considerations:
The study was conducted in accorded with the principles of the Declaration of Helsinki and with the ICH Guidelines for Good Clinical Practice.The study protocol was submitted and approved by the St. Michael's Hospital's Research Ethics Board before beginning the study (REB# 17-098).The study was registered on clinicaltrials.gov(NCT03215316).

Data set included in this study
Including the cases recruited during Sep 2017 -Jan 2020, we have found 35 analyzable cases to be used as a validation set for the MAFAI VENT study.
Table S1: Baseline ventilator settings, parameters, and lung mechanics at baseline in the overall population, non-EFLT and EFLT groups (using PEEP reduction from 5 cmH2O to ZEEP).
Definition of abbreviations: Crs = Compliance of the respiratory system; FiO2 = Fraction of inspired oxygen; PEEP = Positive end-expiratory pressure.Categorical variables are described as number (percentage); continuous variables are described as mean ± SD or median (interquartile range), as appropriate.
* Using any of the following drugs at the time of waveform collection: midazolam, propofol, dexmedetomidine, fentanyl, morphine † Total n = 210 using assist/controlled mode (n = 182 in non EFLT group and n = 28 in EFLT group) ‡ Lung mechanics measurements at ZEEP with 2-seconds end-inspiratory and end-expiratory pauses.When applying PEEP (changing from ZEEP to PEEP ≥ 5 cmH2O): • There was 4.5% of cases with NO EFLT at ZEEP who developed NEW EFLT (This was 3.4% of the total cases)  , 1977).

Table E1:
The 2 x 2 contingency table for agreements between the simplified "delta Vte only" criterion for the detection of EFLT, i.e., a delta Vte of less than 20% when performing PEEP reduction from 5 cmH2O to ZEEP during the VCV mode; VS the "full criteria" considering both the overlapping flow curve and the delta Vte (as used in our primary analysis).
• The positive and negative predictive value of "delta Vte only" methods are 94.9% (85.8% -98.3%) and 100% (98.7% -100%), respectively.and a dedicated pneumotachometer (ICU-Lab system; KleisTek Engineering, Bari, Italy).Panel B2: Early EFLT in patients with fixed / very severe obstruction.Panel C: Late EFLT.In #MV324, only the terminal part of the testbreath flow curve showed subtle convergence to the reference-breath curve while the Rex method could clearly detect an EFLT.This implies a higher sensitivity of the Rex method.Remark: Rex curves calculated from the data recorded by PB980 show lower slope at the initial part (asterisks) when compared to the data recorded by sensors those were attached at the wye-piece, e.g., ICU-lab and Hamilton's ventilator (daggers).This probably reflects the phase-shift between the pressure and the flow data due to gas decompression in the circuits.

Simplified criteria (delta
Development of EFLT criteria for the PEEP reduction manoeuvre Section S5: Development of EFLT criteria for the Rex method Section S6: FLOWLY study (validation set for Rex analysis)

Figure S1 :Figure S2 :Figure S3 :Figure S4 :
Figure S1: Waveform data analyses in more details Figure S2: The flow diagram of the patients Figure S3: Differences of lung mechanics and Rex agreements from short and long pauses Figure S4: Rex calculations in different breaths in a patient with EFLT Figure S5: The differences of inspiratory resistance between subtypes of EFLT

Figure E1 :
Figure E1: More examples of Rex curves

Figure E2 :
Figure E2: PEEPi in non-EFLT cases does not affect the Rex curve figure on the left).Thus, the parallel of the test curves and the reference curves must also be considered.
1. Rex analysis from a representative non-EFLT case.This came from the breaths at ZEEP with an end-expiratory pause, up to 3 breaths per case.2. In order to estimate the Rex value of the constant portion, we performed a linear fitting equation to the portion after the elbow to yield a near-horizontal straight line.An average value of this straight line is the surrogate value of the Rex.

Figure S1 :
Figure S1: Waveform data analyses in more details.The flow and pressure data from the PB840/980 ventilator (a sampling rate of 50 Hz) were recorded using a serial terminal freeware Termite version 3.4 (Informatie-Technologisch Bureau CompuPhase, Bussum, Netherlands).The data from the Hamilton G5/S1 (31.25 Hz) was recorded by Hamilton Datalogger v5.0 (Hamilton Medical AG, Bonaduz, Switzerland).Panel A: The data were imported to MAFAI VENT waveform analyzer v 2.74 (Mahidol University, Bangkok, Thailand).This is a macro-based software developed by the first author (D.J.) and run on Excel 2019 (Microsoft Corp., WA, USA).Panel B: Analysis of PEEP reduction manoeuvre, showing the overlapped flow-volume loops of the test breath and the reference breath.The percentage of the overlap was calculated (the red dashed-box).Panel C: The Rex method.We transformed the flow and pressure data from time-based value to the volume-based value (one datapoint every 2 mL of volume exhaled) using linear extrapolation from the two adjacent data-points.In order to avoid the artifacts at the end of expiration (with very low flow, which will cause the Rex to have extreme fluctuation), we omitted the flow data within the last 5% of the exhaled Vt.With userspecified Crs, the software calculated the Rex value and smoothened the data by 19 data-points moving-average to generate a Rex curve (the blue-green curve).The percentage of Vte that the Rexi value was higher than the Rin + 10 value was shown (the blue dashed-box).
Figure S2: The flow diagram of the patients.

Figure S3 :
Figure S3:The differences of lung mechanics when using a pragmatic 0.2-0.3seconds end-inspiratory pause (a short pause) VS a longer 2-seconds pause (a long pause) at ZEEP and the agreements of EFLT results using these different durations of pause.Panel A: The Bland-Altman plots of Crs as measured by a short VS long pause from 431 cases.Panel B: The Bland-Altman plots of Pplat as measured by a short VS long pause from 431 cases.Panel C: Agreements between a long-pause Rex method and the standardized PEEP reduction method in the original dataset (MAFAI VENT).Panel D: Agreements between a long-pause Rex method and a short-pause Rex method in the original dataset (MAFAI VENT).
(D) Agreements between the Rex method using a 2-seconds (long) end-inspiratory pause and a short (0

Figure S4 :
Figure S4: Rex calculations in different breaths with the premeasured Crs in a patient with EFLT.Panel A: The pressure-time and the flow-time curves using VCV constant flow with end-inspiratory pause of 0.3 seconds.Following a PEEP reduction manoeuvre (PEEP5 in Breath #1 to ZEEP in Br #2), an endexpiratory pause performed in Br #7 revealed PEEPi of 4.4 cmH2O and Crs = 35.0mL/cmH2O.Panel B: The Rex calculation using the Crs from the same breath.There is a marked increment of Rex at the end of expiration beyond the plateau of Rin, signifies the presence of EFLT.Panel C: The Rex calculation in another breath (Br #4) using the premeasured Crs = 35.0from Br #7.The Rex curve is identical to that of the Br #7 showing the characteristics of EFLT.Panel D: The Rex calculation in the test breath of PEEP reduction manoeuvre (Br #2).This also shows an identical curve of Rex with the characteristics of EFLT.Moreover, it demonstrates the relationship to the flow change during the PEEP reduction manoeuvre, i.e., the Rex began to rise at the point where the test flow curve started a convergence into the reference flow curve (the two-headed arrow with an asterisk).

Figure S5 :
Figure S5: The differences of inspiratory resistance (Rin), measured with the standard 2-seconds endinspiratory pause at ZEEP, between non-EFLT and the proposed subtypes of EFLT.The early EFLT (severe / fixed obstruction type) has the highest Rin, followed by the non-severe early EFLT.Overall comparisons by one-way ANOVA showed statistically significant differences between groups with Pvalue < 0.001.Asterisks indicate statistically significance by Student's T-test (P < 0.05).Total n = 311 cases.

Figure E1 :
Figure E1: More examples of Rex curves.Data were obtained from PB840/980 ventilators, unless otherwise specified.Panel A: Non-EFLT.Panel B1: Early EFLT.Note the almost-identical Rex curves obtained from a PB980and a dedicated pneumotachometer (ICU-Lab system; KleisTek Engineering, Bari, Italy).Panel B2: Early EFLT in patients with fixed / very severe obstruction.Panel C: Late EFLT.In #MV324, only the terminal part of the testbreath flow curve showed subtle convergence to the reference-breath curve while the Rex method could clearly detect an EFLT.This implies a higher sensitivity of the Rex method.Remark: Rex curves calculated from the data recorded by PB980 show lower slope at the initial part (asterisks) when compared to the data recorded by sensors those were attached at the wye-piece, e.g., ICU-lab and Hamilton's ventilator (daggers).This probably reflects the phase-shift between the pressure and the flow data due to gas decompression in the circuits.

Figure E2 :
Figure E2:The presence of PEEPi in non-EFLT cases does not affect the Rex curve.Panel A: Pressuretime and flow-time waveforms from patient #MV306 showing an incomplete expiration (the blue arrows), causing PEEPi (4.4 cmH2O at ZEEP, the orange arrow).Panel B: The flow-volume curve of the PEEP reduction manoeuvre (from set PEEP = 5 cmH2O to ZEEP, an asterisk in panel A) and the Rex curve from the test breath.The PEEP reduction manoeuvre shows no significant overlap of the test-breath flow on the threshold envelope, indicating no EFLT.The Rex curve also shows a constant, non-EFLT pattern.Thus PEEPi, in this case, was caused solely by a high respiratory rate and a relatively short expiratory time, not by EFLT.

these calculations, the sample size required for our study was 334 cases.
The extension of the study has been approved by Ramathibodi hospital's Committee for Research.Among different methods for EFLT detection, e.g., negative expiratory pressure, manual abdominal compression, interrupter technique; we had chosen the PEEP reduction manoeuvre as a reference test.The PEEP reduction manoeuvre requires no specialized apparatus and it is independent from the operators [Ref E4], making this the most suitable method for a clinical study.One large clinical cohort study had also implemented this manoeuvre for studying EFLT, supporting the feasibility of the method [Ref E5].
For the continuity correction [Ref E7], the additional number needed in the non-obese group = 1 ( 1 × | 1 −  0 |) ⁄ = 61 cases, and the additional number needed in the obese group = 4 cases.From

Section S4: development of EFLT criteria for PEEP the reduction manoeuvre Section S4: Development of EFL T criteria for the PEEP reduction manoeuvre
Starting from a higher set PEEP would make the PEEP reduction test

Table S2 :
Data were valid in n = 335 for overall population, n = 279 for non-EFLT, and n = 56 for EFLT group The presence of EFLT of the same patient at ZEEP and at PEEP level ≥ 5 cmH2O, as determined by Rex analysis.Total n = 440*, and the P-value is < 0.001 (McNemar paired analysis).

Table S3 :
The 2 x 2 contingency table for agreements between the Rex method and the 5cmH2O PEEP reduction method in the validation dataset (FLOWLY study).

Table S4 :
Characteristics of patients in the validation set for Rex analysis (FLOWLY study), as classified by the PEEP reduction manoeuvre from clinical PEEP to clinical PEEP -5 cmH2O.
* Data available in n =31 (27 in non-EFLT group and 4 in EFLT group) † A patient could have multiple diseases ‡ The set PEEP level where the lung mechanics, intrinsic PEEP, and EFLT were determined.This was clinical PEEP -5 cmH2O.§ Intrinsic PEEP = Total PEEP -Set PEEP

Table S5 :
The distribution of the anatomical site of pathology between each subtype of EFLT.
* e.g.-Acute exacerbation of COPD (airway) due to pneumonia (parenchyma) -Asthmatic attack (airway) in obese patient (chest wall) † e.g.A patient without any previous history of airway disease, had no wheezing or rhonchi on the physical examination record, and the CXR or CT chest was clear, without any pleural or chest wall lesion seen

Table E2 :
Response to external PEEP application among patients with 2 subtypes of EFLT as determined by the Rex analysis performed at ZEEP.This included patients with initial set PEEP > 5 cmH2O, which had been excluded in the main analysis † Applied PEEP level was set to 5 cmH2O or by clinician's initial settings without prior measurement of PEEPi at ZEEP (i.e., the applied PEEP was not systematically set at 80-100% of PEEPi at ZEEP) ‡ Intrinsic PEEP (PEEPi) = Total PEEP -Set PEEP § Determined by the Rex analysis result that became non-EFLT at the applied PEEP level *